Iizuka Mana, Tsuboi Hiroto, Matsuo Naomi, Asashima Hiromitsu, Hirota Tomoya, Kondo Yuya, Iwakura Yoichiro, Takahashi Satoru, Matsumoto Isao, Sumida Takayuki
Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-0006, Japan;
Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan; and.
J Immunol. 2015 Jan 1;194(1):56-67. doi: 10.4049/jimmunol.1401118. Epub 2014 Nov 19.
The nuclear receptor retinoic acid-related orphan receptor (ROR)γt is required for the generation of Th17 cells, which are involved in various autoimmune diseases, including Sjögren's syndrome (SS). However, the pathological role of RORγt in SS remains to be elucidated. The present study was designed to clarify the role of RORγt in the pathogenesis of sialadenitis-like SS. Histological analysis of RORγt transgenic (Tg) mice was determined, and then Tg mice developed severe spontaneous sialadenitis-like SS. The analysis of infiltrating cells showed that most infiltrating cells were CD4(+) T cells. RORγt-overexpressing CD4(+) T cells induced sialadenitis as a result of transferred CD4(+) T cells from Tg mice into Rag2(-/-) mice. The examination of IL-17-deficient Tg mice indicated that IL-17 was not essential for the development of sialadenitis. The number of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells was significantly decreased in Tg mice, and CD25 expression and IL-2 stimulated STAT5 activation were inhibited in Treg cells. The inhibitory function of Treg cells of Tg mice was equal to that of wild-type mice in vitro. The abundant Treg cells of Tg mice could suppress the development of sialadenitis, but the reduced Treg cells of Tg mice could not inhibit the induction of sialadenitis in Rag2(-/-) mice transferred with effector cells from Tg mice. These results suggest that both RORγt-overexpressed CD4(+) T cells and reduced Treg cells might contribute to the development of SS-like sialadenitis.
核受体视黄酸相关孤儿受体（ROR）γt是生成Th17细胞所必需的，Th17细胞参与包括干燥综合征（SS）在内的多种自身免疫性疾病。然而，RORγt在SS中的病理作用仍有待阐明。本研究旨在阐明RORγt在涎腺炎样SS发病机制中的作用。对RORγt转基因（Tg）小鼠进行了组织学分析，结果显示Tg小鼠出现了严重的自发性涎腺炎样SS。对浸润细胞的分析表明，大多数浸润细胞是CD4(+) T细胞。将Tg小鼠的CD4(+) T细胞转移到Rag2(-/-)小鼠中，结果显示过表达RORγt的CD4(+) T细胞可诱导涎腺炎。对IL-17缺陷型Tg小鼠的检查表明，IL-17对涎腺炎的发展并非必需。Tg小鼠中CD4(+)CD25(+)Foxp3(+)调节性T（Treg）细胞的数量显著减少，Treg细胞中的CD25表达和IL-2刺激的STAT5激活受到抑制。Tg小鼠Treg细胞的抑制功能在体外与野生型小鼠相当。Tg小鼠中丰富的Treg细胞可抑制涎腺炎的发展，但Tg小鼠中减少的Treg细胞不能抑制在转入Tg小鼠效应细胞的Rag2(-/-)小鼠中涎腺炎的诱导。这些结果表明，RORγt过表达的CD4(+) T细胞和减少的Treg细胞可能都有助于SS样涎腺炎的发展。
